Organic-inorganic hybrid chiral sorbent and process for the preparation thereof

ABSTRACT

The present invention provides an organic-inorganic hybrid chiral sorbent for chiral resolution of various racemic compounds viz. racemic mandelic acid, 2-phenyl propionic acid, diethyl tartrate, 2,2′-dihydroxy-1,1′-binaphthalene (BINOL) and cyano chromene oxide with excellent chiral separation (enantiomeric excess, 99%) in case of mandelic acid under medium pressure column chromatography. These optically pure enantiomers find applications as intermediates in pharmaceutical industries.

FIELD OF THE INVENTION

The present invention relates to an organic-inorganic hybrid chiralsorbent. More particularly it relates to optically pure covalentlybonded amino alcohol to mesoporous silica as chiral selector for chiralresolution of various racemic compounds, viz. racemic mandelic acid,2-phenyl propionic acid, diethyl tartrate,2,2′-dihydroxy-1,1′-binaphthalene (BINOL) and cyano chromene oxide undermedium pressure column chromatography. The present invention furtherrelates to a process for the preparation of organic-inorganic hybridchiral sorbent. These optically pure enantiomers find applications asintermediates in pharmaceutical industries.

BACKGROUND OF THE INVENTION

Resolution of chiral molecules is required in many areas of research. Asenzymes and other biological receptor molecules are stereo-specific,enantiomers of a racemic compound may interact with them in a differentmanner. Consequently, two enantiomers of a racemic compound havedifferent pharmacological activities in many instances. In order todiscern these differing effects, the biological activity of eachenantiomer needs to be studied separately.

This has contributed significantly towards the requirement ofenantiomerically pure compounds particularly in pharmaceutical industryand thereby the needs to focus on chiral separation using techniqueslike chiral chromatography. Various attempts have been made in the pastfor the development of different stationary phases; for example A.Bielejewska et al. Chem. Anal. (Warsaw) 47 (2002) 419 has reportedβ-cyclodextrin (p-CD) and permethylated β-cyclodextrin for use ofchromatographic separation of mandelic acid and its esters of differentaliphatic carbon chain length by reverse phase HPLC. The drawbacks ofthis process are; (i) β-cyclodextrin alone does not recognizeenantiomers of mandelic acid; (ii) stationary phase needs to bepermethylated for achieving high chiral separation; (iii) reaction hasto be conducted in reverse phase.

S. P. Mendez et al. J. Anal. At. Spectrom. 13 (1998) 893. reported theresolution of D,L-selenomethionine derivatives of OPA (O-phthalaldehyde)and NDA (2,3-naphthalenedicarboxaldehyde) to their respectiveenantiomers by HPLC on a β-CD chiral column using conventionalfluorimetric detection. The drawbacks of this process are; (i) In thisstudy, the amino acid was derivatized using o-phthalaldehyde ornaphthalene-2,3-dicarboxaldehyde to allow conventional fluorimetricdetection. Such a derivatization step, however, is undesirable becauseit prolongs the sample preparation time, and requires additionalvalidation because it may be a potential source of contamination, mayinduce racemization or may complicate the separation.

L. S. Karen et al. Analyst 125 (2000) 281 disclosed the work based on acommercially available HPLC column with a chiral crown ether basedstationary phase to perform enantiomeric separations of selenoaminoacids without derivatization. The drawbacks of this process are; (i) theneed to have dilute perchloric acid as mobile phase for such a column;(ii) The separation of the enantiomers is temperature sensitive.

C. A. L. Ponce de Leon et al. J. Anal. At. Spectrom. 15 (2000) 1103describes the enantiomeric separation of nine selenoamino acidsencountered in selenium-enriched yeast using a crown ether column. Thedrawbacks of this process are; (i) this reaction involves acidiccondition to get effective separation; (ii) The separation processrequires lower temperature (18-22° C.) for complete resolution; (iii)the non-polar amino acids may not elute from the column, therefore, abalance between temperature and elution of non-polar compounds isrequired for an optimum separation.

S. P. Mendez et al. J. Anal. At. Spectrom. 15 (2000) 1109 described theuse of teicoplanin-bonded chiral stationary phase (Chirobiotic T) toresolve a variety of underivatized aminoacids. Teicoplanin is aglycopeptide antibiotic which contains 20 chiral centers. The drawbacksof this process are; (i) Teicoplanin is a toxic and naturally occurringcomplex molecule therefore cannot be easily tuned for variousapplications (ii) due to the presence of many glycosidic linkages it isprone to hydrolysis and/or alteration in conformation thereby change inoptical properties under the elution conditions (iii) this separationprocess requires pH adjustment about 4 and 7; (iv) separation has to beconducted in reverse phase.

M. Raimondo et al. Chem. Commun. (1997) 1343 used mesoporoussilica-based MCM-41 coated on GC capillary columns, as chiral stationaryphase to separate different organic molecules The drawbacks of thisprocess are; (i) That separation indeed occurs within the MCM-41cavities and by a mechanism depending on the proton affinities of thecompounds.

M. Grun et al. J. Chromatogr. A 740 (1996) 1 described the behavior ofsilica, alumina, titania, zirconia and the novel mesoporousaluminosilicate MCM-41 in normal-phase high-performance liquidchromatography under comparable conditions. MCM-41 shows someinteresting features as compared to mesoporous crystalline and amorphousoxides. The drawbacks of this process are; (i) This work includes onlycomparison of an ordered mesoporous aluminosilicate, silica, alumina,titania and zirconia in normal-phase high-performance liquidchromatography; (ii) it requires very large column (250×4 mm).

V. A. Soloshonok, Angew. Chem., Int. Ed. 45 (2006) 766), reported thework based on achiral silica as column packing material for remarkableseparation of enantiomers of perfluoroalkyl keto compounds throughcolumn chromatography. The drawbacks of this process are; (i) onlytrifluoromethyl group containing compounds are separated. (ii) variationin results is found with changing the solvents. (iii) In the case ofpreferential homochiral association, the situation is bit subtle as theformation of dimer will result in different number of enantiomeric(S)(S) and (R)(R) pairs with identical scalar properties. These dimerstherefore cannot be separated.

J. H. Kennedy, J. Chromatogr. A 725 (1996) 219 disclosed chiralstationary phases based on polysaccharide derivative coated on silicafor chiral separation of different compounds containing carbonyl groupand other aromatic ring containing compounds. The drawbacks of thisprocess are; (i) Derivatization of carboxylic acids or eluent modifierssuch as acetic acid or diethyl amine is required in this system;.(ii)Polysaccharide phases based chiral stationary phase is not predictableand capable of separating both t-acid and n-basic type compounds.

X. Huang et al. Analytical Science 21 (2005) 253 and S. Rogozhin et al.German Patent 1 932 190 (1969); Chem. Abstr., 72 (1970) 90875c havedescribed the use of chiral copper metal complex supported on silica asstationary phase for separation DL-selenomethionine in buffered solutionat pH, 5.5 along with methanol as mobile phase. The drawbacks of thisprocess is (i) This separation technique requires 200×4.6 mm i.d.stainless-steel column; (ii) only underivatized amino acids wereresolved on it; (iii) the use of methanol doesn't favor the resolutionof DL-selenomethionine; (iv) higher temperature gives some de-activationeffect of some biological sample.

J. Bergmann et al. Anal. Bioanal. Chem. 378 (2004) 1624 and M. M. Bayonet al. J. Anal. At. Spectrom. 16(9) (2001) 945 disclosed a fast andsensitive method for the determination of the absolute configuration ofSe-amino acids by derivatization process at room temperature byreversed-phase high-performance liquid chromatography-inductivelycoupled plasma-mass spectrometry. The drawbacks of these process are;(i) separation can be possible in reversed phase HPLC-inductivelycoupled plasma-mass spectrometry; (ii) Detection limits of about 4microg L(-1) were obtained; (iii) The derivetization of enantiomers ofselenomethionine is necessary. (iv) The final operating conditionsinvolved the use of 50% (v/v) MeOH at pH 5.3 (acetic acid—sodiumacetate).

H. Kosugi et al. Chem. Commun. (1997) 1857 described synthesis of(−)-epibatidine and its intermediates by medium pressure liquidchromatography by using achiral silica gel column (Si-10; eluted with3:1 hexane-EtOAc; UV (254 nm) and RI detectors). The drawbacks of thisprocess are; (i) In this system there is no mechanism of the separation:(ii) It includes only synthesis of (−)-epibatidine and itsintermediates; (iii) only hydroxy acetal was separated through achiralcolumn chromatography.

S. P. Mendez et al. J. Anal. At. Spectrom. 14 (1999) 1333 describedchiral resolution and speciation of DL-selenomethionine enantiomers bycapillary gas chromatography (GC) using an L-valine-tert-butylamidemodified polydimethylsiloxane as chiral stationary phase The drawbacksof this process are; (i) good resolution was achieved in the highertemperature range only from 100-160° C.; (ii) requires He as carriergas; (iii) separation is more difficult for complex biological samples.

R. Vespalec et al. Anal. Chem. 67 (1995) 3223; K. L. Sutton et al.Analyst 125 (2000) 231; S. P. Mendez et al. Anal. Chim. Acta 416 (2000)1; J. A. Day et al. J. Anal. At. Spectrom. 17 (2002) 27 describescapillary electrophoresis as a tool for the enantiomeric separationselenium containing amino acids, by derivatization process usingcapillary electrophoresis with UV absorbance detection. The drawbacks ofthis process are; (i) This separation technique has been used toseparate the enantiomers of selenoamino acids by the addition of chiraladditives to the electrophoretic buffer; (ii) UV absorbance detectionwas used in these studies and required the derivatization of theselenoamino acids to permit detection; (iii) UV absorbance detection,without sample pre-concentration, was not sensitive enough to permit thedetection of the low levels of selenoamino acids present in complexsamples; (iv) applied voltage and pH value gives variation in separationresults; (v) buffer system was chosen for good resolution; (vi) additionof methanol to the buffer is required for improved resolution.

B. V. Ernholt et al. Eur. J. Chem. 6 (2000) 278) described the synthesisand enzymatic separation of 1-Azafagomine through achiral regular columnchromatography. The drawbacks of this process are; (i) enzymeticseparation requires different buffer solutions; (ii) the conversion andenantiomeric excess is affected by varying the solvents, enzymes and itsconcentration; (iii) low enantiomeric excess was achieved throughachiral column chromatography by loading 51% compound.

A. Goswami et al., Z Tetrahedron Asymmetry, 16 (2005) 1715 disclosedenzymatic separation of (±)-sec-butlylamine, lipase and proteases usingether, heptane or dacane as solvent and vinyl butyrate or ethyl,butyrate as acylating agent. The drawbacks of this process are; (i)enzymes shows very low enantio-selectivity; (ii) it's a time consumingprocess (more than 7 days); (iii) solvent, such as acetonitrile,cyclohexane, toluene, methyl-t-butyl ether, 2-methyl-2-pentanol, ethylcaprate is required for this system. Mitsuhashi Kazuya et at in U.S.Pat. No. 278,268 Oct. 23, 2002 disclosed a method for the synthesis ofoptically active mandelic acid derivatives by enzymatic separation. Thedrawbacks of this process are; (i) microorganism is essential togenerate the (R)-mandelic acid derivative or (S)-mandelic acidderivative; (ii) requires appropriate buffer solution.

Mori Takao et al. U.S. Pat. No. 142,914 Oct. 29, 1993 disclosed aprocess for preparing D-mandelic acid by converting L-mandelic acid intobenzoylformic acid followed by stereoselectively reducing it intoD-mandelic acid. The drawbacks of this process are; (i) The isolationand collection of microbial cells from culture broth is complicated;(ii) buffer solution is required for maintaining pH; (iii) it is timeconsuming process.

Endo Takakazu et at in U.S. Pat. No. 677,175 Mar. 29, 1991 disclosedprocess for producing (R)-(−)-mandelic acid or a derivative throughenzymatic separation. The drawbacks of this process are; (i) hydrolysisof mandelonitrile is necessary; (ii) requires neutral or basic reactionsystem to produce the (R)-(−)-mandelic acid; (iii) requires expensiveuse of microorganism and Ghisalba Oreste et at in U.S. Pat. No. 360,802Jun. 2, 1989 described process for the preparation of R- orS-2-hydroxy-4-phenylbutyric acid in very high enantiomeric purity byenzymatic separation. Disadvantage of this process are; (i) Thereduction of the substrate is effected by the so-called final reductase;(ii) suitable as biocatalysts are only purified enzymes; (iii)regeneration of enzyme is complicated.

Hashimoto Yoshihiro et at in U.S. Pat. No. 764,295 Dec. 12, 1996,reported a process for producing an alpha-hydroxy acid or analpha-hydroxyamide from an aldehyde and prussic acid with amicroorganism. The drawbacks of this process are; (i) deactivation ofmicroorganism within a short period of time at higher and lowertemperature; (ii) high concentration and high yield is difficult toobtain for alpha-hydroxy acid or alpha-hydroxyamide; (iii) the reactionrate is lowered with an increase in the concentration of thealpha-hydroxy acid or alpha-hydroxyamide product as a result, thereaction does not proceed to completion.

Endo Takakazu et al in U.S. Pat. No. 904,335 Jun. 25, 1992 described aprocess for producing (R),(S)-mandelic acid or a derivative thereof frommandelonitrile using a microorganism belonging to the genus Rhodococcus.The drawbacks of this process are; (i) chiral reagents and microorganismare more expensive; (ii) this method is industrially non-advantageousfor producing (R)-(−)-mandelic acid or derivatives; (iii) hydrogenasesproduced by these bacteria are not always satisfactory.

R. Charles et al. J. Chromatogr. 298 (1984) 516 described the separationof ¹⁴C labelled nicotine through totally achiral column chromatography.The drawbacks of this process are; (i) it requires buffer solution toadjust the pH; (ii) peak-splitting phenomenon was caused by somecomponents of the cation-exchange column or mobile phase.

V. A. Soloshonok et al. J. Fluorine Chemistry, In Press disclosed theself-disproportionation chromatography (SDC) involves the separation oftrifluoromethyl group containing compounds and used totally achiralsilica as column packing. The drawbacks of this process are; (i)variations in results are found with changing the solvents. (ii) In thecase of preferential homochiral association, the situation is bit subtleas the formation of dimmer will result in different number ofenantiomeric (S)(S) and (R)(R) pairs with identical scalar properties.These dimers therefore cannot be separated.

OBJECTIVES OF THE INVENTION

The main object of the present invention is to provide anorganic-inorganic hybrid chiral sorbent

Another object of the invention is to provide a process for thepreparation of organic-Inorganic hybrid chiral sorbent.

Yet another object of the present invention is to provide a process forchiral resolution of racemic compounds using optically pure aminoalcohols covalently attached on mesoporous silica as chiral selector forchiral resolution of various racemic compounds viz. racemic mandelicacid, 2-phenyl propionic acid, diethyl tartrate,2,2′-dihydroxy-1,1′-binaphthalene (BINOL) and cyano chromene.

Yet another object of the present invention is to provide chiralresolution of racemic compounds using optically pure amino alcoholcovalently attached on mesoporous silica as chiral selector forachieving high Enantiomeric Excess (ee) (99%) at room temperature.

Yet another object of the present invention is to provide chiralresolution of racemic compounds using optically pure amino alcoholcovalently attached on mesoporous silica as chiral selector under mediumpressure slurry system.

Still another object of the present invention is to provide chiralresolution of racemic compounds using optically pure amino alcoholcovalently attached on mesoporous silica as chiral selector under mediumpressure (0.5 kp/cm²) column chromatography.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides an organic-inorganic hybridchiral sorbent comprising amino alcohol covalently bonded to the surfaceof mesoporous silica material.

In an embodiment of the present invention the amino alcohol used isamino propyl alcohol.

In another embodiment of the present invention the porous silicamaterial used is having porosity in the range of 37 to 100 Å and isselected from the group consisting of MCM-41, SBA-15 and MCF-48.

In yet another embodiment the product obtained in the present inventionis represented by the group of following chiral sorbent selected from(S)-aminopropyl alcohol@silica-41, (R)-aminopropyl alcohol@silica-41,(S)-aminopropyl alcohol@silica-15, (R)-aminopropyl alcohol@silica-15,(S)-aminopropyl alcohol@silica-F, (R)-aminopropyl alcohol@silica-F,(S)—N-methyl aminopropyl alcohol@silica-41, (R)—N-methyl aminopropylalcohol@silica-41, (S)—N,N′dimethyl aminopropyl alcohol@silica-41,(S)—N,N′dimethyl aminopropyl alcohol@silica-15 and (S)—N-methylaminopropyl alcohol@silica-15

In yet another embodiment of the invention the chiral sorbent is usefulfor the separation of racemic mixture of compounds selected from thegroup consisting of mandelic acid, 2-phenyl propionic acid, diethyltartrate, 2,2′-dihydroxy-1,1′-binaphthalene (BINOL) and cyano chromeneoxide.

The present invention further provides a process for the preparation ofan organic-inorganic hybrid chiral sorbent, the said process comprisingthe steps of:

-   -   a) silylating the chiral epoxide with a silylating agent in an        organic solvent with a molar ratio of chiral epoxide to        silylating agent in the range of 1:1 to 1:2.5, in the presence        of an inorganic base,    -   b) refluxing, the above said mixture obtained in step (a) under        an inert atmosphere for a period of 8 to 16 hours, followed by        filtration to obtain the resultant filterate,    -   c) refluxing, the above said filterate obtained in step (b) with        mesoporous silica, under inert atmosphere for a period of about        35 to 55 hours, followed by filtration and washing of the        resultant solid product with toluene by known methods,    -   d) reacting the resultant washed product obtained in step (c)        with aniline or substituted aniline in toluene, under reflux,        under an inert atmosphere for a period of 8 to 16 hours,        followed by filtration and washing off the resultant product        with toluene and extracting the desired chiral sorbent in a        solution mixture of toluene and isopropanol by known methods to        obtain the desired product of organic-inorganic hybrid chiral        sorbent.

In yet another embodiment the chiral epoxide used in step(a) is selectedfrom the group consisting of propene oxide, 1-chloro-2,3-epoxypropane,1-fluoro-2,3-epoxypropane, 1-bromo-2,3-epoxypropane,1-methyl-2,3-epoxypropane, 1-methoxy-2,3-epoxypropane and1-nitro-2,3-epoxypropane.

In yet another embodiment the silylating agent used in step(a) isselected from the group consisting of chloropropyl triethoxysilane,chloropropyltrimethoxy, nitropropyltriethoxysilane,aminopropyltriethoxysilane and aminopropyltrimethoxy silane.

In yet another embodiment the inorganic base used in step (a) isselected from the group consisting of sodium carbonate, potassiumcarbonate, rubidium carbonate and cesium carbonate.

In yet another embodiment the organic solvent used in step(a) isselected from the group consisting of ethanol, methanol, isopropanol,acetone, acetonitrile, toluene, tetrahydrofuran, dichloroethane anddichloromethane.

In yet another embodiment the mesoporous silica used in step (c) isselected from the group consisting of MCM-41, SBA-15 and MCF-48.

In yet another embodiment the inert atmosphere used is provided by usinginert gas selected from nitrogen, argon and helium.

In yet another embodiment the molar amount of aniline or substitutedaniline with respect to chiral epoxide is in the range of 1:1 to 1:2.

In yet another embodiment the substituted aniline used is selected fromthe group consisting of nitroaniline, chloroaniline, methoxyaniline andmethylaniline.

In yet another embodiment the amount of mesoporous silica used is in therange of 0.8 to 12 g/mmol of chiral epoxide.

In yet another embodiment the chiral sorbent obtained in step(d) isrepresented by the group of following sorbents: mandelic acid, 2-phenylpropionic acid, diethyl tartrate, 2,2′-dihydroxy-1,1′-binaphthalene(BINOL) and cyano chromene oxide.

In yet another embodiment the chiral sorbent obtained is useful for theseparation of racemic mixtures of compound selected from the groupconsisting of mandelic acid, 2-phenyl propionic acid, diethyl tartrate,2,2′-dihydroxy-1,1′-binaphthalene (BINOL) and cyano chromene oxide.

In yet another embodiment the enantiomeric excess of racemates obtainedis in the range of 30 to 99%.

In still another embodiment the maximum enantiomeric excess obtained formandelic acid with aminopropylalcohol@silica sorbent is about 99%.

DESCRIPTION OF THE INVENTION

According to the present invention describes the preparation oforganic-inorganic hybrid chiral sorbent, which comprises of

-   -   i) silylation of chiral epoxide in the concentration range of        2.557 to 25.57 mmol with aminopropyl        triethoxysilane/N-methylaminopropyl triethoxysilane in the        concentration range of 2.55 to 25.57 mmol in the presence of        K₂CO₃/Na₂CO₃ in the concentration range of 5.1 to 51 mmol in dry        tetrahydrofuran;    -   ii) refluxing the reaction mixture in the step i) under N₂Ar/He        atmosphere in the time range of 8 to16 h;    -   iii) filtrating the reaction mixture of step ii) to obtain clear        solution;    -   iv) refluxing the clear solution of step (iii) with mesoporous        silica in the range of 2 g to 20 g in dry toluene under N₂/Ar/He        atmosphere for a period of 35 to 55 h;    -   v) filtration of reaction mixture of step iv) to obtain solid        material, followed by washing with toluene and Soxhlet        extraction in toluene;    -   vi) reacting the washed material obtained in step (v) with        aniline/substituted anilines in the concentration range of 5 to        50 mmol under reflux condition in N₂/Ar/He atmosphere for a        period of 8-16 h in toluene;    -   vii) filtration of solid sorbent in step vi) followed by washing        with toluene, Soxhlet extraction in toluene/isopropanol in the        range (9:1 to 7:3) and dried in vacuum;    -   viii) Taking the chiral column packing material from step vii)        in the concentration range of 0.128 to 0.512 mol %    -   ix) Making slurry of chiral packing material to step viii) by        using hexane/isopropanol as column packing solvents in the ratio        of (9.5:0.5) to (8:2) and packing in a 260×16 mm glass column;    -   x) loading of analyte on the packed column from step ix) as        solid or dissolving in hexane/isopropanol ratio (1:1) in the        concentration range 0.50 to 3.00 mol %;    -   xi) elution of solvents through column in step x) using        hexane/isopropanol in the ratio of (9.5:0.5) to (8:2) using        medium-pressure (0.25-0.75 kp/cm²) of nitrogen/argon/helium at        room temperature;    -   xii) collecting the chromatographic fractions (1-12), (13-24)        and (25-36) from step xi) in the range of 2 to 6 ml per fraction        with an increment of 2 ml after 12 fractions;    -   xiii) maintaining the medium-pressure (0.25-0.75 kp/cm²) of        nitrogen/argon/helium at room temperature through out the step        xii)    -   xiv) examining each collected fractions from step xi to xiii) on        an appropriate chiral HPLC column.

The synthesis process of amino alcohol modified silica was conducted onlaboratory scale in a 100 ml three-necked round bottom flask fitted withan efficient water condenser using S-(+)-epichlorohydrin, 3-aminopropyltriethoxysilane, aniline and silica. The medium pressure columnchromatography was carried out by making slurry of (S)-aminoalcohol@silica 1 in hexane and isopropanol (9:1) was packed in a 260×16mm glass column using medium-pressure (0.5 kp/cm²) of nitrogen at roomtemperature. The analyte solution in isopropanol/hexane (1:1) was loadedon thus packed column that was equilibrated for 1 h. The elution offractions was done at the pressure mentioned above. Each fraction wassubjected to HPLC analysis using an appropriate chiral column. Differentanalytical grade compounds were used as an analytes. The absoluteconfiguration of different compound was determined by the comparison ofHPLC profile with authentic samples.

The separation process according to the present invention was carriedout by using amount of analyte in the range of 10 to 30 mg, preferablyusing 2 g amino alcohol immobilized on silica as column packing materialat medium-pressure (0.5 kp/cm²) of nitrogen at room temperature. Higherseparation of mandelic acid was obtained when the amount of analyte wasmore than 10 mg. The chiral products were characterized by thecomparison of HPLC profile with authentic samples. In the preferredembodiment, the pressure of the column is maintained (0.25-0.75 kp/cm²)of nitrogen at room temperature. In accordance with the presentinvention, the chiral amino alcohol immobilized on silica plays a veryvital role in achieving better separation of analytes. The amino alcoholused to separate analyte is 2 g. With low quantity of amino alcoholmodified silica the separation is sluggish. The use of optimal quantityamino alcohol modified silica (2 g) is essential as it definitelyseparates the different analyte.

In carrying out the present invention, the time required for thechromatographic separation of analytes is more than 7 h to achievehigher enantiomeric excess. The time of separation may be varied byincreasing pressure, it was observed that decreasing the time ofchromatographic separation below 5 h resulted in lower separation ofanalyte

The present invention relates to the preparation of chiral compoundssuitable for various applications. These chiral compounds were separatedfrom racemic compounds by medium pressure chromatographic separationusing amino alcohol as selector at medium-pressure (0.5 kp/cm²) ofnitrogen at room temperature. The chromatographic separation of racemiccompounds was found to be higher than that reported in literature wherethe separation depends on i) derivatization of stationary phase as wellas analyte, ii) pH of eluents iii) high temperature requirement thatresult into diffusional problems, reproducibility and difficulty intheir reuse. The method of present invention does not require anyspecial device.

The inventive steps adopted in the present invention are:—

-   (i) generating chirality on inorganic silica surface by covalently    binding the simple and readily available chiral organic compounds    through silanol groups present on the silica surface.-   (ii) Using surface bound chiral amino alcohol as a selector for the    chromatographic separation of different compounds at room    temperature.-   (iii) the resolution of racemic compound is carried out at    medium-pressure (0.5 kp/cm²) of nitrogen;

In a typical chromatographic resolution run, the appropriate aminoalcohol as selector, hexane/isopropanol as eluents was packed into260×16 mm glass column using medium-pressure slurry system (0.5 kp/cm²)at room temperature. The analyte solution in isopropanol/hexane (1:1)was loaded on thus packed column that was equilibrated for 1 h. Eachfraction was subjected to HPLC analysis using an appropriate chiralcolumn.

The following examples are given by way of illustration of the presentinvention and therefore should not be construed to limit the scope ofthe present invention.

Example-1

Step 1:

(2′S)—N-(2′,3′-epoxypropyl)-3-(aminopropyl)-triethoxysilane

(S)-(−)-epichlorohydrine (0.2 ml), 3-aminopropyl triethoxy silane (0.598g), potassium carbonate (0.705 g) and dry tetrahydrofuran were chargedin a 3-necked 50 ml round bottom flask equipped with a mechanicalstirrer, addition funnel and a reflux condenser connected to a nitrogeninlet. The resulting mixture was stirred at room temperature for 10minutes and followed by refluxing the mixture for 12 h. The reactionmixture was filtered under an inert atmosphere. Solvent from thefiltrate was removed by the dry nitrogen draft

Yield; (0.674 g, 95%).

Step 2:

(S)-amino propyl epoxy@silica-41

The product of step 1 (0.674) was dissolved in dry toluene in a 3-necked50 ml round bottom flask in an inert atmosphere. The dissolved mass wastreated with MCM-41 (2.0 g) for 48 h. at the refluxing temperature oftoluene. The reaction mass was filtered and washed with dry toluene forseveral time then dried under vacuum. The dried material was subjectedto Soxhlet extraction with dry toluene for 10 h followed by drying thesample under vacuum. Yield; (2 g, loading 22.5% by TGA)

Step 3:

(S)-aminopropyl alcohol@silica-41

The epoxy product from the step 2 (22.5% loading, 2 g) was treated withaniline (455 μl) in 10 ml dry toluene in an inert atmosphere. Thesuspension was refluxed for 12 h. The reaction mixture was cooled toroom temperature and the solid was filtered, washed repeatedly with drytoluene and subjected to Soxhlet extraction with toluene and isopropanol(7:3) for 10 h. Finally the sample was dried under vacuum at 40° C.Yield; (2 g, loading 25.6% by TGA).

Example-2

Step 1:

(2′R)—N-(2′,3′-epoxypropyl)-3-(aminopropyl)-triethoxysilane

(R)-(−)-epichlorohydrine (0.2 ml), 3-aminopropyl triethoxy silane (0.598g), potassium carbonate (0.705 g) and dry tetrahydrofuran were reactedand processed in the manner it was done in step 1 of the example 1.Yield (0.680 g, 96%).

Step 2:

(R)-aminopropyl epoxy@silica-41

The product of step 1 (0.674) was dissolved in dry toluene in 3-necked50 ml round bottom flash in an inert atmosphere. Then this dissolvedmass was treated with MCM-41 (2.0 g) for 48 h at refluxing temperature.The reaction mixture was processed as per the method given in step 2 ofthe example 1. (2 g, loading 22.0% by TGA)

Step 3:

(R)-aminopropyl alcohol@silica-41

The epoxy product from the step 2 (22.0% loading, 2 g) was treated withaniline (455 μl) in 10 ml dry toluene in inert atmosphere. Thesuspension was treated as per the method given in step 3 of theexample 1. Yield (2 g, loading 25.0% by TGA).

Example-3

Step 1:

(2′S)—N-(2′,3′-epoxypropyl)-3-(aminopropyl)-trimethoxysilane

(S)-(−)-epibromohydrine (0.2 ml), 3-aminopropyl trimethoxy silane (0.598g), potassium carbonate (0.705 g) and dry diethyl ether were charged ina 3-necked 50 ml round bottom flask equipped with a mechanical stirrer,addition funnel and a reflux condenser connected to a nitrogen inlet.The resulting mixture was stirred at room temperature for 10 minutes andfollowed by refluxing the mixture for 10 h. The reaction mixture wasfiltered under inert atmosphere. Solvent from the filtrate was removedby the dry nitrogen draft. Yield (0.65 g, 95%).

Step 2:

(S)-aminopropyl epoxy@silica-15

The product of step 1 (0.65 g) was dissolved in dry toluene in 3-necked50 ml round bottom flask in an inert atmosphere. Then this dissolvedmass was treated with SBA-15 (2.0 g) for 48 h. at refluxing temperature.The reaction mass was filtered and washed with dry toluene for severaltime then dried under vacuum. The dried material was subjected toSoxhlet extraction with dry toluene for 10 h followed by drying thesample under vacuum. (2.2 g, loading 24.0% by TGA)

Step 3:

(S)-aminopropyl alcohol@silica-15

The epoxy product from the step 2 (24.0% loading, 2 g) was treated withaniline (500 μl) in 10 ml dry toluene in an inert atmosphere. Thesuspension was refluxed for 12 h. The reaction mixture was cooled toroom temperature and the solid was filtered, washed repeatedly with drytoluene and subjected to the soxhlet extraction with toluene andisopropanol (7:3) for 10 h. Finally the sample was dried under vacuum at40° c. (2 g, loading 26.5%).

Example-4

Step 1:

(2′R)—N-(2′,3′-epoxypropyl)-3-(aminopropyl)-tributoxysilane

(R)-(−)-epichlorohydrine (0.2 ml), 3-aminopropyl tributoxysilane (0.598g), Sodium carbonate (0.700 g) and dry tetrahydrofuran were charged in a3-necked 50 ml round bottom flask equipped with a mechanical stirrer,addition funnel and a reflux condenser connected to a nitrogen inlet.The resulting mixture was stirred at room temperature for 10 minutes andfollowed by refluxing the mixture for 12 h. The reaction mixture wasfiltered under inert atmosphere. Solvent from the filtrate was removedby the dry nitrogen draft: yield (0.60 g, 94%).

Step 2:

(R)-aminopropyl epoxy@silica-15

The product of step 1 (0.674) was dissolved in dry toluene in 3-necked50 ml round bottom flash in inert atmosphere. Then this dissolved masswas treated with SBA-15 (2.0 g) for 48 h. at refluxing temperature.Reaction was further processed as per the step 2 of the example 3. (2 g,loading 26.0% by TGA).

Step 3:

(R)-aminopropyl alcohol@silica-15

The epoxy product from the step 2 (26.0% loading, 2 g) was treated withaniline (500 μl) in 10 ml dry toluene in inert atmosphere. Thesuspension was refluxed for 12 h. The reaction mixture was cooled toroom temperature and the solid was filtered, washed repeatedly with drytoluene and subjected to the soxhlet extraction with toluene andisopropanol (7:3) for 10 h. Finally the sample was dried under vacuum at40° C. (2 g, loading 26.2%).

Example-5

Step 1:

(2′S)—N-(2′,3′-epoxypropyl)-3-(aminopropyl)-trimethoxysilane

Synthesized as per the method given in step 1 of the example 1.

Step 2:

(S)-aminopropyl epoxy@silica-F

The product of step 1 (0.674 g) was dissolved in dry toluene in 3-necked50 ml round bottom flask in an inert atmosphere. Then this dissolvedmass was treated with MCF (2.0 g) for 48 h. at refluxing temperature.The reaction mass was filtered and washed with dry toluene for severaltime then dried under vacuum. The dried material was subjected toSoxhlet extraction with dry toluene for 10 h followed by drying thesample under vacuum.(2.2 g, loading 27.0% by TGA)

Step 3:

(S)-aminopropyl alcohol@silica-F

The epoxy product from the step 2 (27.0% loading, 2 g) was treated withaniline (600 μl) in 10 ml dry toluene in inert atmosphere. Thesuspension was refluxed for 12 h. The reaction mixture was cooled toroom temperature and the solid was filtered, washed repeatedly with drytoluene and subjected to the soxhlet extraction with toluene andisopropanol (7:3) for 10 h. Finally the sample was dried under vacuum at40° C. (2 g, loading 27.6%).

Example-6

Step 1:

(2′R)—N-(2′,3′-epoxypropyl)-3-(aminopropyl)-trimethoxysilane

This material was synthesized as per the method described in step 1 ofthe example 1.

Step 2:

(R)-aminopropyl epoxy@silica-F

The product of step 1 (0.674 g) was dissolved in dry toluene in 3-necked50 ml round bottom flash in inert atmosphere. Then this dissolved masswas treated with MCF (2.0 g) and processed as per the method of step 2of example 5. Yield; 2 g, loading 26.5% by TGA.

Step 3:

(R)-aminopropyl alcohol@silica-F

The epoxy product from the step 2 (26.5% loading, 2 g) was treated withaniline (600 μl) in 10 ml dry toluene in an inert atmosphere and thereaction was processed as per the step 3 of the example 5. (Yield; 2 g,loading 27.0%).

Example-7

Step 1:

(2′S)—N′-(2′,3′-epoxypropyl)-3-(N-methylaminopropyl)-trimethoxysilane

(S)-(−)-epichlorohydrine (0.2 ml), 3-N-methylaminopropyl trimethoxysilane (0.700 g), potassium carbonate (0.705 g) and dry toluene werecharged in a 3-necked 50 ml round bottom flask equipped with amechanical stirrer, addition funnel and a reflux condenser connected toa nitrogen inlet. The resulting mixture was stirred at RT for 10 minutesand followed by refluxing the mixture for 16 h. The reaction mixture wasfiltered under inert atmosphere. Solvent from the filtrate was removedby the dry nitrogen draft: yield (0.715 g, 96%).

Step 2:

(S)—N-methyl aminopropyl epoxy@silica-41

The product of step 1 (0.700 g) was dissolved in dry toluene in 3-necked50 ml round bottom flask in an inert atmosphere. The reaction mixturewas treated with MCM-41 (2 g) for 48 h. at the refluxing temperature oftoluene. The reaction mass was filtered and washed with dry toluene forseveral time then dried under vacuum. The dried material was subjectedto Soxhlet extraction with dry toluene for 10 h followed by drying thesample under vacuum (2.2 g, loading 20.5% by TGA)

Step 3:

(S)—N-methyl aminopropyl alcohol@silica-41

The epoxy product from the step 2 (20.5% loading, 2 g) was treated withaniline (455 μl) in 10 ml dry toluene in an inert atmosphere. Thesuspension was refluxed for 12 h. The reaction mixture was cooled toroom temperature and the solid was filtered, washed repeatedly with drytoluene and subjected to the soxhlet extraction with toluene andisopropanol (7:3) for 10 h. Finally the sample was dried under vacuum at40° C. (2 g, loading 25.6%).

Example-8

Step 1:

(2′R)—N′-(2′,3′-epoxypropyl)-3-(N-methylaminoaminopropyl)-trimethoxysilane

(R)-(−)-epichlorohydrine (0.2 ml), 3-N-methylaminopropyl trimethoxysilane (0.598 g), sodium carbonate (0.705 g) and dry methanol werecharged in a 3-necked 50 ml round bottom flask equipped with amechanical stirrer, addition funnel and a reflux condenser connected toa nitrogen inlet. The reaction was processed as per the method given instep 1 of the example 7. Yield (0.725 g, 97%).

Step 2:

(R)—N-methyl aminopropyl epoxy@silica-41

The product of step 1 (0.700 g) was dissolved in dry toluene in 3-necked50 ml round bottom flask in inert atmosphere. Then this dissolved masswas treated with MCM-41 (2.0 g) in the manner described in step 2 of theexample 7. (2.0 g, loading 21.0% by TGA)

Step 3:

(R)—N-methyl aminopropyl alcohol@silica-41

The epoxy product from the step 2 (21.1% loading, 2 g) was treated withaniline (455 μl) in 10 ml dry toluene in an inert atmosphere. Thereaction was processed as per the method described in step 3 of theexample 7. Yield (2 g, loading 25.0%).

Example-9

Step 1:

(2′S)—N′-(2′,3′-epoxypropyl)-3-(N-methylaminopropyl)-trimethoxysilane

This material was synthesized by following the method given in step 1 ofthe example 7.

Step 2:

(S)—N-methyl aminopropyl epoxy@silica-15

The product of step 1 (0.674 g) was dissolved in dry toluene in 3-necked50 ml round bottom flask in an inert atmosphere. Then this dissolvedmass was treated with SBA-15 (2.0 g) for 48 h. at refluxing temperature.The reaction mass was filtered and washed with dry toluene for severaltime then dried under vacuum. The dried material was subjected toSoxhlet extraction with dry toluene for 10 h followed by drying thesample under vacuum. Yield (2.4 g, loading 23.5% by TGA).

Step 3:

(S)—N-methyl aminopropyl alcohol@silica-15

The epoxy product from the step 2 (23.5% loading, 2 g) was treated withaniline (600 μl) in 10 ml dry toluene in an inert atmosphere. Thesuspension was refluxed for 12 h. The reaction mixture was cooled toroom temperature and the solid was filtered, washed repeatedly with drytoluene and subjected to the soxhlet extraction with toluene andisopropanol (7:3) for 10 h. Finally the sample was dried under vacuum at40° C. (2 g, loading 26.8%).

Example-10

Step 1:

(2′S)—N′-(2′,3′-epoxypropyl)-3-(N-methylaminopropyl)-trimethoxysilane

This material was prepared by the method described in the step 1 of theexample 7.

Step 2:

(S)—N-methyl aminopropyl epoxy@silica-41

this material was prepared by following the procedure given in step 2 ofthe example 7.

Step 3:

(S)—N,N′ dimethyl aminopropyl alcohol@silica-41

The epoxy product from the step 2 (20.5% loading, 2 g) was treated withN-methylaniline (600 μl) in 10 ml dry toluene in an inert atmosphere.The suspension was refluxed for 18 h. The reaction mixture was cooled toroom temperature and the solid was filtered, washed repeatedly with drytoluene and subjected to the soxhlet extraction with toluene andisopropanol (7:3) for 10 h. Finally the sample was dried under vacuum at40° C. (2 g, loading 23.5%).

Example-11

Step 1:

(2′S)—N′-(2′,3′-epoxypropyl)-3-(N-methylaminopropyl)-trimethoxysilane

This material was prepared by the method described in the step 1 of theexample 7.

Step 2:

(S)—N-methyl aminopropyl epoxy@silica-41

This material was prepared by following the procedure given in step 2 ofthe example 7.

Step 3:

(S)—N-methyl aminopropyl alcohol@silica-41

The epoxy product from the step 2 (20.5% loading, 2 g) was treated with4-methyl aniline (600 μl) in 10 ml dry toluene in an inert atmosphere.The suspension was refluxed for 18 h. The reaction mixture was cooled toroom temperature and the solid was filtered, washed repeatedly with drytoluene and subjected to the soxhiet extraction with toluene andisopropanol (7:3) for 10 h. Finally the sample was dried under vacuum at40° C. (2 g, loading 23.5%).

Example-12

Step 1:

(2′S)—N′-(2′,3′-epoxypropyl)-3-(N-methylaminopropyl)-trimethoxysilane

This material was prepared by the method described in the step 1 of theexample 7.

Step 2:

(S)—N-methyl aminopropyl epoxy@silica-41

This material was prepared by following the procedure given in step 2 ofthe example 7.

Step 3:

(S)—N-methyl aminopropyl alcohol@silica-41

The epoxy product from the step 2 (20.5% loading, 2 g) was treated with4-chloro aniline (600 μl) in 10 ml dry toluene in an inert atmosphere.The suspension was refluxed for 18 h. The reaction mixture was cooled toroom temperature and the solid was filtered, washed repeatedly with drytoluene and subjected to the soxhlet extraction with toluene andisopropanol (7:3) for 10 h. Finally the sample was dried under vacuum at40° C. (2 g, loading 23.5%).

Example-13

Step 1:

(2′S)—N′-(2′,3′-epoxypropyl)-3-(N-methylaminopropyl)-trimethoxysilane

This material was prepared by the method described in the step 1 of theexample 7.

Step 2:

(S)—N-methyl aminopropyl epoxy@silica

This material was prepared by following the procedure given in step 2 ofthe example 7.

Step 3:

(S)—N-methyl aminopropyl alcohol@silica-41

The epoxy product from the step 2 (20.5% loading, 2 g) was treated with4-methoxy aniline (600 μl) in 10 ml dry toluene in an inert atmosphere.The suspension was refluxed for 18 h. The reaction mixture was cooled toroom temperature and the solid was filtered, washed repeatedly with drytoluene and subjected to the soxhlet extraction with toluene andisopropanol (7:3) for 10 h. Finally the sample was dried under vacuum at40° C. (2 g, loading 23.5%).

Example-14

Step 1:

(2′S)—N′-(2′,3′-epoxypropyl)-3-(N-methylaminopropyl)-trimethoxysilane

This material was prepared by the method described in the step 1 of theexample 5.

Step 2:

(S)-aminopropyl epoxy@silica-F

this material was prepared by following the procedure given in step 2 ofthe example 5.

Step 3:

(S)-aminopropyl alcohol@silica-F

The epoxy product from the step 2 (20.5% loading, 2 g) was treated with4-methoxy aniline (600 μl) in 10 ml dry toluene in an inert atmosphere.The suspension was refluxed for 18 h. The reaction mixture was cooled toroom temperature and the solid was filtered, washed repeatedly with drytoluene and subjected to the soxhlet extraction with toluene andisopropanol (7:3) for 10 h. Finally the sample was dried under vacuum at40° C. (2 g, loading 23.5%).

Example-15

Step 1:

(2′S)—N′-(2′,3′-epoxypropyl)-3-(N-methylaminopropyl)-trimethoxysilane

This material was prepared by the method described in the step 1 of theexample 5.

Step 2:

(S)-aminopropyl epoxy@silica-F

this material was prepared by following the procedure given in step 2 ofthe example 5.

Step 3:

(S)-aminopropyl alcohol@silica-F

The epoxy product from the step 2 (20.5% loading, 2 g) was treated with4-chloro aniline (600 μl) in 10 ml dry toluene in an inert atmosphere.The suspension was refluxed for 18 h. The reaction mixture was cooled toroom temperature and the solid was filtered, washed repeatedly with drytoluene and subjected to the soxhlet extraction with toluene andisopropanol (7:3) for 10 h. Finally the sample was dried under vacuum at40° C. (2 g, loading 23.5%).

Example-16

Step 1:

(2′S)—N′-(2′,3′-epoxypropyl)-3-(N-methylaminopropyl)-trimethoxysilane

This material was prepared by the method described in the step 1 of theexample 5.

Step 2:

(S)-aminopropyl epoxy@silica-F

this material was prepared by following the procedure given in step 2 ofthe example 5.

Step 3:

(S)-aminopropyl alcohol@silica-F

The epoxy product from the step 2 (20.5% loading, 2 g) was treated with4-methyl aniline (600 μl) in 10 ml dry toluene in an inert atmosphere.The suspension was refluxed for 18 h. The reaction mixture was cooled toroom temperature and the solid was filtered, washed repeatedly with drytoluene and subjected to the soxhlet extraction with toluene andisopropanol (7:3) for 10 h. Finally the sample was dried under vacuum at40° C. (2 g, loading 23.5%).

Example-17 Step 1:(2′S)—N′-(2′,3′-epoxypropyl)-3-(N-methylaminopropyl)-trimethoxysilane

This material was prepared by the method described in the step 1 of theexample 9.

Step 2:

(S)—N-methylaminopropyl epoxy@silica-15

This material was prepared by following the procedure given in step 2 ofthe example 9.

Step 3:

(S)—N,N′-dimethyl aminopropyl alcohol@silica-15

The epoxy product from the step 2 (20.5% loading, 2 g) was treated with4-methyl aniline (600 μl) in 10 ml dry toluene in an inert atmosphere.The suspension was refluxed for 18 h. The reaction mixture was cooled toroom temperature and the solid was filtered, washed repeatedly with drytoluene and subjected to the soxhlet extraction with toluene andisopropanol (7:3) for 10 h. Finally the sample was dried under vacuum at40° C. (2 g, loading 23.5%).

Example-18

Step 1:

(2′S)—N′-(2′,3′-epoxypropyl)-3-(N-methylaminopropyl)-trimethoxysilane

This material was prepared by the method described in the step 1 of theexample 9.

Step 2:

(S)—N-methyl aminopropyl epoxy@silica-15

This material was prepared by following the procedure given in step 2 ofthe example 9.

Step 3:

(S)—N-methyl aminopropyl alcohol@silica-15

The epoxy product from the step 2 (20.5% loading, 2 g) was treated with4-methoxy aniline (600 μl) in 10 ml dry toluene in an inert atmosphere.The suspension was refluxed for 18 h. The reaction mixture was cooled toroom temperature and the solid was filtered, washed repeatedly with drytoluene and subjected to the soxhlet extraction with toluene andisopropanol (7:3) for 10 h. Finally the sample was dried under vacuum at40° C. (2 g, loading 23.5%).

Example-19

Step 1:

(2′S)—N′-(2′,3′-epoxypropyl)-3-(N-methylaminopropyl)-trimethoxysilane

This material was prepared by the method described in the step 1 of theexample 9.

Step 2:

(S)—N-methylaminopropyl epoxy@silica-15

This material was prepared by following the procedure given in step 2 ofthe example 9.

Step 3:

(S)—N-methyl aminopropyl alcohol@silica-15

The epoxy product from the step 2 (20.5% loading, 2 g) was treated with4-chloro aniline (600 μl) in 10 ml dry toluene in an inert atmosphere.The suspension was refluxed for 18 h. The reaction mixture was cooled toroom temperature and the solid was filtered, washed repeatedly with drytoluene and subjected to the soxhlet extraction with toluene andisopropanol (7:3) for 10 h. Finally the sample was dried under vacuum at40° C. (2 g, loading 23.5%).

Example-20

Step 1:

(2′S)—N-(2′,3′-epoxypropyl)-3-(aminopropyl)-triethoxysilane

(S)-(−)-Ephedrine (0.2 ml), 3-aminopropyl triethoxy silane (0.598 g),potassium carbonate (0.705 g) and dry tetrahydrofuran were charged in a3-necked 50 ml round bottom flask equipped with a mechanical stirrer,addition funnel and a reflux condenser connected to a nitrogen inlet.The resulting mixture was stirred at RT for 10 minutes and followed byrefluxing the mixture for 12 h. The reaction mixture was filtered underan inert atmosphere. Solvent from the filtrate was removed by the drynitrogen draft: Yield; (0.674 g, 95%).

Step 2:

(S)-aminopropyl epoxy@silica-41

The product of step 1 (0.674) was dissolved in dry toluene in a 3-necked50 ml round bottom flask in an inert atmosphere. The dissolved mass wastreated with MCM-41 (2.0 g) for 48 h. at the refluxing temperature oftoluene. The reaction mass was filtered and washed with dry toluene forseveral time then dried under vacuum. The dried material was subjectedto Soxhlet extraction with dry toluene for 10 h followed by drying thesample under vacuum. Yield; (2 g, loading 22.5% by TGA)

Step 3:

(S)-aminopropyl alcohol@silica-41

The epoxy product from the step 2 (22.5% loading, 2 g) was treated withaniline (455 μl) in 10 ml dry toluene in an inert atmosphere. Thesuspension was refluxed for 12 h. The reaction mixture was cooled toroom temperature and the solid was filtered, washed repeatedly with drytoluene and subjected to Soxhlet extraction with toluene and isopropanol(7:3) for 10 h. Finally the sample was dried under vacuum at 40° c.Yield; (2 g, loading 25.6% by TGA).

Example-21

Step 1:

(2′S)—N-(2′,3′-epoxypropyl)-3-(aminopropyl)-triethoxysilane

(S)-(−)-PsaudoEphedrine (0.2 ml), 3-chloro propyl triethoxy silane(0.598 g), potassium carbonate (0.705 g) and dry tetrahydrofuran werecharged in a 3-necked 50 ml round bottom flask equipped with amechanical stirrer, addition funnel and a reflux condenser connected toa nitrogen inlet. The resulting mixture was stirred at RT for 10 minutesand followed by refluxing the mixture for 12 h. The reaction mixture wasfiltered under an inert atmosphere. Solvent from the filtrate wasremoved by the dry nitrogen draft: Yield; (0.674 g, 95%).

Step 2:

(S)-aminopropyl epoxy@silica-41

The product of step 1 (0.674) was dissolved in dry toluene in a 3-necked50 ml round bottom flask in an inert atmosphere. The dissolved mass wastreated with MCM-41 (2.0 g) for 48 h. at the refluxing temperature oftoluene. The reaction mass was filtered and washed with dry toluene forseveral time then dried under vacuum. The dried material was subjectedto Soxhlet extraction with dry toluene for 10 h followed by drying thesample under vacuum. Yield; (2 g, loading 22.5% by TGA)

Step 3:

(S)-aminopropyl alcohol@silica-41

The epoxy product from the step 2 (22.5% loading, 2 g) was treated withaniline (455 μl) in 10 ml dry toluene in an inert atmosphere. Thesuspension was refluxed for 12 h. The reaction mixture was cooled toroom temperature and the solid was filtered, washed repeatedly with -drytoluene and subjected to Soxhlet extraction with toluene and isopropanol(7:3) for 10 h. Finally the sample was dried under vacuum at 40° C.Yield; (2 g, loading 25.6% by TGA).

Example-22

In a medium pressure chromatographic column, slurry of (S)-aminopropylalcohol@silica 1 (0.128 mol %) in hexane and isopropanol (9:1) waspacked in a 260×16 mm glass column using medium-pressure (0.5 kp/cm²) ofnitrogen at room temperature. The solid racemic mandelic acid (3.00 mol%) was loaded on packed column that was equilibrated for 1 h. Theelution of fractions was done at the pressure mentioned above. Eachfraction was subjected to HPLC analysis using an appropriate ChiralcelOD column, eluent hexane/isopropanol (9:1) at 220 nm. The enantiomericexcess of mandelic acid found 7.4%.

Example-23

To a medium pressure chromatographic column, slurry of (S)-aminopropylalcohol@silica 1 (0.128 mol %) in hexane and isopropanol (9:1) waspacked in a 260×16 mm glass column using medium-pressure (0.5 kp/cm²) ofnitrogen at room temperature. The solid racemic mandelic acid (3.00 mol%) was loaded on packed column that was equilibrated for 1 h. Theelution of fractions was done at the pressure mentioned above. Eachfraction was subjected to HPLC analysis using an appropriate ChiralcelOD column, eluent hexane/isopropanol (9:1) at 220 nm. The enantiomericexcess, enantiomeric excess of mandelic acid found 7.4%.

Example-24

To a medium pressure chromatographic column, slurry of (S)-aminopropylalcohol@silica 1 (0.512 mol %) in hexane and isopropanol (9:1) waspacked in a 260×16 mm glass column using medium-pressure (0.5 kp/cm²) ofnitrogen at room temperature. The solid racemic mandelic acid (1.50 mol%) was loaded on packed column that was equilibrated for 1 h. Theelution of fractions was done at the pressure mentioned above. Eachfraction was subjected to HPLC analysis using an appropriate ChiralcelOD column, eluent hexane/isopropanol (9:1) at 220 nm. The enantiomericexcess of mandelic acid found 8.3%.

Example-25

To a medium pressure chromatographic column, slurry of (S)-aminopropylalcohol@silica 1 (0.512 mol %) in hexane and isopropanol (9:1) waspacked in a 260×16 mm glass column using medium-pressure (0.5 kp/cm²) ofnitrogen at room temperature. The racemic mandelic acid (1.50 mol %)dissolved in isopropanol/hexane (1:1) was loaded on packed column thatwas equilibrated for 1 h. The elution of fractions was done at thepressure mentioned above. Each fraction was subjected to HPLC analysisusing an appropriate Chiralcel OD column, eluent hexane/isopropanol(9:1) at 220 nm. The enantiomeric excess of mandelic acid found 99.4%.

Example-26

To a medium pressure chromatographic column, slurry of (S)-aminopropylalcohol@silica 1 (0.486 mol %) in hexane and isopropanol (9:1) waspacked in a 260×16 mm glass column using medium-pressure (0.5 kp/cm²) ofnitrogen at room temperature. The racemic mandelic acid (1.58 mol %)dissolved in isopropanol/hexane (1:1) was loaded on packed column thatwas equilibrated for 1 h. The elution of fractions was done at thepressure mentioned above. Each fraction was subjected to HPLC analysisusing an appropriate Chiralcel OD column, eluent hexane/isopropanol(9:1) at 220 nm. The enantiomeric excess of mandelic acid found 99.0%.

Example-27

To a medium pressure chromatographic column, slurry of (S)-aminopropylalcohol@silica 1 (0.479 mol %) in hexane and isopropanol (9:1) waspacked in a 260×16 mm glass column using medium-pressure (0.5 kp/cm²) ofnitrogen at room temperature. The racemic mandelic acid (1.60 mol %)dissolved in isopropanol/hexane (1:1) was loaded on packed column thatwas equilibrated for 1 h. The elution of fractions was done at thepressure mentioned above. Each fraction was subjected to HPLC analysisusing an appropriate Chiralcel OD column, eluent hexane/isopropanol(9:1) at 220 nm. The enantiomeric excess of mandelic acid found 98.8%.

Example-28

To a medium pressure chromatographic column, slurry of (S)-aminopropylalcohol@silica 1 (0.512 mol %) in hexane and isopropanol (9:1) waspacked in a 260×16 mm glass column using medium-pressure (0.5 kp/cm²) ofnitrogen at room temperature. The racemic mandelic acid (0.50 mol %)dissolved in isopropanol/hexane (1:1) was loaded on packed column thatwas equilibrated for 1 h. The elution of fractions was done at thepressure mentioned above. Each fraction was subjected to HPLC analysisusing an appropriate Chiralcel OD column, eluent hexane/isopropanol(9:1) at 220 nm. The enantiomeric excess, enantiomeric excess ofmandelic acid found 98.5%

Example-29

To a medium pressure chromatographic column, slurry of MCM-41 (0.512 mol%) in hexane and isopropanol (9:1) was packed in a 260×16 mm glasscolumn using medium-pressure (0.5 kp/cm²) of nitrogen at roomtemperature. The racemic mandelic acid (0.50 mol %) dissolved inisopropanol/hexane (1:1) was loaded on thus packed column that wasequilibrated for 1 h. The elution of fractions was done at the pressurementioned above. Each fraction was subjected to HPLC analysis using anappropriate Chiralcel OD column, eluent hexane/isopropanol (9:1) at 220nm. No separation of mandelic acid was found.

Example-30

To a medium pressure chromatographic column, slurry of (S)-aminopropylalcohol@silica 1 (0.512 mol %) in hexane and isopropanol (8:2) waspacked in a 260×16 mm glass column using medium-pressure (0.5 kp/cm²) ofnitrogen at room temperature. The racemic2,2′-dihydroxy-1,1′-binaphthalene (BINOL) (0.50 mol %) dissolved inisopropanol/hexane (1:1) was loaded on packed column that wasequilibrated for 1 h. The elution of fractions was done at the pressurementioned above. Each fraction was subjected to HPLC analysis using anappropriate Chiralpak AD column, eluent hexane/isopropanol (8:2) at 254nm. The enantiomeric excess, enantiomeric excess of2,2′-dihydroxy-1,1′-binaphthalene (BINOL) found 19.5%.

Example-31

To a medium pressure chromatographic column, slurry of (S)-aminopropylalcohol@silica 1 (0.512 mol %) in hexane and isopropanol (9:1) waspacked in a 260×16 mm glass column using medium-pressure (0.5 kp/cm²) ofnitrogen at room temperature. The racemic cyanochromene oxide (CNCR)(0.50 mol %) dissolved in isopropanol/hexane (1:1) was loaded on packedcolumn that was equilibrated for 1 h. The elution of fractions was doneat the pressure mentioned above. Each fraction was subjected to HPLCanalysis using an appropriate Chiralcel OD column, eluenthexane/isopropanol (9:1) at 254 nm. The enantiomeric excesscyanochromene oxide (CNCR) of found 3.8%.

Example-32

To a medium pressure chromatographic column, slurry of (S)-aminopropylalcohol@silica 1 (0.512 mol %) in hexane and isopropanol (8:2) waspacked in a 260×16 mm glass column using medium-pressure (0.5 kp/cm²) ofnitrogen at room temperature. The solution of racemic diethyl-tartrate(0.50 mol %) in isopropanol/hexane (1:1) was loaded on packed columnthat was equilibrated for 1 h. The elution of fractions was done at thepressure mentioned above. Each fraction was subjected to HPLC analysisusing an appropriate Chiralpak AD column, eluent hexane/isopropanol(8:2) at 220nm. The enantiomeric excess of diethyl-tartrate found 11.5%.

Example-33

To a medium pressure chromatographic column, slurry of (S)-aminopropylalcohol@silica 1 (0.512 mol %) in hexane and isopropanol (9.5:0.5) waspacked in a 260×16 mm glass column using medium-pressure (0.5 kp/cm²) ofnitrogen at room temperature. The solution of racemic 2-phenyl propionicacid (0.50 mol %) in isopropanol/hexane (1:1) was loaded on thus packedcolumn that was equilibrated for 1 h. The elution of fractions was doneat the pressure mentioned above. Each fraction was subjected to HPLCanalysis using an appropriate Chiralcel OD column, eluenthexane/isopropanol/formic acid (9:8.1) at 254nm. The enantiomeric excessof 2-phenyl propionic acid found 33.5%

Example-34

The same procedure as exemplified in example 1 was repeated with variousracemic compounds viz., 2-phenyl propionic acid, diethyl tartrate,2,2′-dihydroxy-1,1′-binaphthalene (BINOL) and cyano chromene oxide undermedium pressure column chromatography. The results are summarized inTable 1 and 2.

TABLE 1 Separation of Mandelic acid varying amount of Mandelic acid andpacking material Amount of Column Loading Mandelic Packing of acidMaterial^(c) Mandelic Absolute Entry m.mol 1(g) acid^(e) (%) Eluent^(f)% ee max^(g) configuration 1 0.099^(a) 0.50 3.0 Hex/IPA = 9:1  7.4 R 20.197^(a) 2.00 1.5 Hex/IPA = 9:1  8.3 R 3 0.197^(b) 2.00 1.5 Hex/IPA =9:1 99.4 R 4 0.197^(b) 1.90 1.5 Hex/IPA = 9:1 99.0 R 5 0.197^(b) 1.871.5 Hex/IPA = 9:1 98.8 R 6 0.066^(b) 2.00 0.5 Hex/IPA = 9:1 98.5 R 70.066^(b) MCM-41^(d) 0.5 Hex/IPA = 9:1 — R + S (50:50%) ^(a)Mandelicacid loaded on column as solid, ^(b)Mandelic acid loaded on column afterdissolving in Isopropanol/Hexane, ^(c)(S)-amino propyl alcohol@silica isused as column packing material ^(d)MCM-41 is used as column packingmaterial (2 gm), ^(e)percentage loading of mandelic acid according tocolumn packing material, ^(f)Hex = hexane, IPA = isopropanol,^(g)Enantiomeric Excess of R-mandelic acid using HPLC chiralcel ODcolumn, eluent Hexane/IPA = 9:1 at 220 nm., ^(h)absolute configurationwere determined by the comparison of HPLC profile with authenticsamples.

TABLE 2 Data for separation of different compounds by flash columnchromatography^(a) Column Name of Sample Packing compound amount^(f)Material % ee Absolute Entry (racemic) (mg) 1 (g) Eluent^(g) maxconfiguration^(h) 8 BINOL^(b) 10 2.0 Hex/IPA = 8:2 19.5 R 9 CNCR^(c) 102.0 Hex/IPA = 9:1 3.8 3S,4S 10 Diethyl 10 2.0 Hex/IPA = 8:2 11.5 2R,3RTartrate^(d) 11 2-phenyl 10 2.0 Hex/IPA = 9.5:0.5 33.5 S Propionicacid^(e) ^(a)All the experiments were conducted under the same conditionunless otherwise stated. Temperature (27° C.), amount of sample m =0.0100 ± 0.0001 g, column diameter d = 16 mm, length = 260 mm,Enantiomeric excess was determined by HPLC analysis by mentionedcolumns. (l = 25 cm, d = 0.46 cm). ^(b)Chiralpak AD column, eluentHexane/IPA = 8:2 at 254 nm. ^(c)Cyanochromene oxide(CNCR) chiralcel ODcolumn, eluent Hexane/IPA = 9:1 at 254 nm. ^(d)Chiralpak AD column,eluent Hexane/IPA = 9:1 at 220 nm. ^(e)Chiralcel OD column, eluentHexane/IPA/Formic acid = 98:2:1 at 254 nm. ^(f)Analyte loaded on columnafter dissolving in Isopropanol/Hexane. ^(g)Hex = hexane, IPA =isopropanol. ^(h)The absolute configuration were determined by thecomparison of HPLC profile with authentic samples.

ADVANTAGES OF THE INVENTION

-   -   Resolution of different compounds is achievable with inexpensive        medium pressure column chromatography.    -   Organic selector based amino alcohol modified silica (2 g) is        sufficient enough for the separation of enantiomers in the        present invention at room temperature.    -   Only smaller quantity of column packing material is required to        carry out for the repeated experiments using medium pressure        column chromatography.    -   Organic solvents like hexane and isopropanol are used as column        packing solvents as well as eluents.    -   Under the defined chromatographic conditions the resolution of        enantiomers is carried out by medium-pressure range from        (0.25-0.75 kp/cm²) of nitrogen at room temperature.    -   Separation chromatography is carried out in air and no prior        oxygen free conditions are required.    -   A simple glass column is required for packing purpose.    -   Using the present invention high resolution of racemates having        excellent enantiomeric excess was achieved within reasonable        time period that makes the process viable for industrial        application.    -   By carrying out the Soxhlet extraction process, the amino        alcohol modified silica can be reused for repeated experiments.

1. An organic-inorganic hybrid chiral sorbent comprising amino alcoholcovalently bonded to the surface of mesoporous silica material.
 2. Aproduct according to claim 1, wherein the amino alcohol used is aminopropyl alcohol.
 3. A product according to claim 1, wherein the poroussilica material used is having porosity in the range of 37 to 100 Å andis selected from the group consisting of MCM-41, SBA-15 and MCF-48.
 4. Aproduct according to claim 1, wherein the product obtained isrepresented by the group of following chiral sorbents: (S)-aminopropylalcohol@silica-41, (R)-aminopropyl alcohol@silica-41, (S)-aminopropylalcohol@silica-15, (R)-aminopropyl alcohol@silica-15, (S)-aminopropylalcohol@silica-F, (R)-aminopropyl alcohol@silica-F, (S)—N-methylaminopropyl alcohol@silica-41, (R)—N-methyl aminopropylalcohol@silica-41, (S)—N,N′dimethyl aminopropyl alcohol@silica-41,(S)—N,N′dimethyl aminopropyl alcohol@silica-15 and (S)—N-methylaminopropyl alcohol@silica-15
 5. A product according to claim 1, whereinthe chiral sorbent is useful for the separation of racemic mixture ofcompound selected from the group consisting of mandelic acid, 2-phenylpropionic acid, diethyl tartrate, 2,2′-dihydroxy-1,1′-binaphthalene(BINOL) and cyano chromene oxide.
 6. A process for the preparation of anorganic-inorganic hybrid chiral sorbent, the said process comprising thesteps of: a) silylating the chiral epoxide with a silylating agent in anorganic solvent with a molar ratio of chiral epoxide to silylating agentof about 1:1 in the presence of an inorganic base in the range of 1:1 to1:2.5, b) refluxing, the above said reaction mixture obtained in step(a) under an inert atmosphere for a period of 8 to 16 hours, followed byfiltration to obtain the resultant filtrate, c) refluxing, the abovesaid filterate obtained in step (b) with mesoporous silica, under inertatmosphere for a period of about 35 to 55 hours, followed by filtrationand washing of the resultant solid product with toluene by knownmethods, d) reacting the resultant washed product obtained in step (c)with aniline or substituted aniline in toluene, under reflux, under aninert atmosphere for a period of 8 to 16 hours, followed by filtrationand washing off the resultant product with toluene and extracting thedesired chiral sorbent in a solution mixture of toluene and isopropanolby known methods to obtain the desired product of organic-inorganichybrid chiral sorbent.
 7. A process according to claim 6, wherein thechiral epoxide used in step(a) is selected from the group consisting ofpropene oxide, 1-chloro-2,3-epoxypropane, 1-fluoro-2,3-epoxypropane,1-bromo-2,3-epoxypropane, 1-methyl-2,3-epoxypropane,1-methoxy-2,3-epoxypropane and 1-nitro-2,3-epoxypropane.
 8. A processaccording to claim 6, wherein the silylating agent used in step(a) isselected from the group consisting of chloropropyl triethoxysilane,chloropropyltrimethoxy, nitropropyltriethoxysilane,aminopropyltriethoxysilane and aminopropyltrimethoxysilane.
 9. A processaccording to claim 6, wherein the inorganic base used in step (a) isselected from the group consisting of sodium carbonate, potassiumcarbonate, rubidium carbonate and cesium carbonate.
 10. A processaccording to claim 6, wherein the organic solvent used in step(a) isselected from the group consisting of ethanol, methanol, isopropanol,acetone, acetonitrile, toluene, tetrahydrofuran, dichloroethane anddichloromethane.
 11. A process according to claim 6, wherein themesoporous silica used in step (c) is selected from the group consistingof MCM-41, SBA-15 and MCF-48.
 12. A process according to claim 6,wherein the inert atmosphere used is provided by using inert gasselected from nitrogen, argon and helium.
 13. A process according toclaim 6, wherein the molar amount of aniline or substituted aniline withrespect to chiral epoxide is in the range of 1:1 to 1:2.
 14. A processaccording to claim 6, wherein the substituted aniline used is selectedfrom the group consisting of nitroaniline, chloroaniline, methoxyanilineand methylaniline.
 15. A process according to claim 6, wherein theamount of mesoporous silica used is in the range of 0.8 to 12 g/mmol ofchiral epoxide.
 16. A process according to claim 6, wherein the chiralsorbent obtained in step(d) is represented by the group of followingsorbents: mandelic acid, 2-phenyl propionic acid, diethyl tartrate,2,2′-dihydroxy-1,1′-binaphthalene (BINOL) and cyano chromene oxide. 17.A process according to claim 6, wherein the chiral sorbent obtained isuseful for the separation of racemic mixtures of compound selected fromthe group consisting of mandelic acid, 2-phenyl propionic acid, diethyltartrate, 2,2′-dihydroxy-1,1′-binaphthalene (BINOL) and cyano chromeneoxide.
 18. A process according to claim 17, wherein the enantiomericexcess of racemates obtained is in the range of 30 to 99%.
 19. A processaccording to claim 18, wherein the maximum enantiomeric excess obtainedfor mandelic acid with aminopropylalcohol@silica sorbent is about 99%.